Project Summary-Abstract: Since its establishment in 2000, the Ohio Valley Node (OVN) has been one of the most productive of NIDA's Clinical Trials Network (CTN) nodes, both in leading and participating in multi-site trials. In this application the OVN has been expanded to be a node of networks: the Ohio Valley Node-Network (OVNN). The OVNN includes eight original OVN sites, which are located in 6 states and treat more than 225,000 patients per year; and three additional practice based research networks (PBRNs). Two are state-wide primary care PBRNs, the Collaborative Ohio Inquiry Network (COIN) and the Wisconsin Research and Education Network (WREN), which, combined, include more than 350 practices and treat more than 4 million patients per year. The third is a state-wide pharmacy PBRN in Indiana, which includes 168 pharmacies that fill 1.5 million prescriptions annually. These Midwestern sites and partnerships will contribute needed diversity to CTN clinical trials. The OVNN Research Core is the driving force of the OVNN and is led by Dr. Winhusen, one of the foremost experts in conducting multi-site addiction clinical trials in clinical practice settings. The OVNN co-investigators include experts in primary care (Elder), emergency medicine (Lyons), and pediatric emergency medicine (Grupp- Phelan) practice-based research. The 7 members of the OVN research-implementation team bring 72 years of combined experience conducting CTN clinical trials. A primary goal of the application is to conduct the research needed to inform clinical practice guidelines for effective substance use disorder (SUD) prevention and treatment in general medical care settings, which are largely lacking but increasingly needed, with a specific focus on research to address the opioid abuse epidemic. Our proposed research agenda includes pragmatic clinical trials testing interventions to predict, prevent, and respond to opioid misuse in primary care; to reduce the reoccurrence of opioid overdose by linking patients treated for an overdose in emergency medicine departments to SUD treatment through a novel peer-based intervention; and to reduce the transmission of HIV and HCV through pharmacy-based testing for buprenorphine-treated patients.